The goal of this project is to apply a novel, well developed cost effective means of drug target and drug discovery to parasitic disease, focusing on Trypanosoma cruzi and Leishmania, the causative agents of Chagas disease and Leishmanaisis respectively. This project will generate comparative compound screens to identify new anti-kinetoplastid compounds that are broadly applicable to both T. cruzi and Leishmania species. The identification of broad-spectrum therapeutics will facilitate later commercialization by significantly increasing the potential market for new therapeutics, an important attribute since most of the afflicted populations are poor. The experimental approach exploits a novel method for identifying compounds that interact specifically with trypanosomal protein targets but not with the human analogs. In this method, T. cruzi, Leishmania sp., and human genes are introduced into yeast, functionally replacing the cognate yeast genes. A collection of these yeast strains, each bearing a different trypanosomatid or human gene (trypanosomatid and human XenoGene arrays), can be used as compound screening platforms in a high through-put bioassay to identify compounds which specifically inhibit the function of the trypanosome targets but not analogous targets in the human XenoGene array. This application also includes a pilot small molecule screen of selected kinetoplastid targets. [unreadable] [unreadable]